TY - JOUR
T1 - Proton pump inhibitors and vascular function
T2 - A prospective cross-over pilot study
AU - Ghebremariam, Yohannes T.
AU - Cooke, John P.
AU - Khan, Fouzia
AU - Thakker, Rahul N.
AU - Chang, Peter
AU - Shah, Nigam H.
AU - Nead, Kevin T.
AU - Leeper, Nicholas J.
N1 - Funding Information:
This pilot study was funded by grants from the Translational Research and Applied Medicine (TRAM) Program in the Department of Medicine at Stanford University [grant number 1144447-121-DHAXB]. This study was also supported in part by grants to JPC from the National Institutes of Health (NIH) [grant numbers 1R01 EY02060901, 1U01 HL100397] and internal funding from the Houston Methodist Research Institute (HMRI). YTG was a recipient of postdoctoral fellowships from the Stanford School of Medicine Dean’s Office [grant number 1049528-149-KAVFB] and the Tobacco-Related Disease Research Program (TRDRP) of the University of California [grant number 20FT-0090]. He is currently supported by the National Heart, Lung, and Blood Institute (NHLBI) [grant number 1K01 HL118683-01] and HMRI [grant number 25150001].
Publisher Copyright:
© The Author(s) 2015.
PY - 2015/8/10
Y1 - 2015/8/10
N2 - Proton pump inhibitors (PPIs) are commonly used drugs for the treatment of gastric reflux. Recent retrospective cohorts and large database studies have raised concern that the use of PPIs is associated with increased cardiovascular (CV) risk. However, there is no prospective clinical study evaluating whether the use of PPIs directly causes CV harm. We conducted a controlled, open-label, cross-over pilot study among 21 adults aged 18 and older who are healthy (n=11) or have established clinical cardiovascular disease (n=10). Study subjects were assigned to receive a PPI (Prevacid; 30 mg) or a placebo pill once daily for 4 weeks. After a 2-week washout period, participants were crossed over to receive the alternate treatment for the ensuing 4 weeks. Subjects underwent evaluation of vascular function (by the EndoPAT technique) and had plasma levels of asymmetric dimethylarginine (ADMA, an endogenous inhibitor of endothelial function previously implicated in PPI-mediated risk) measured prior to and after each treatment interval. We observed a marginal inverse correlation between the EndoPAT score and plasma levels of ADMA (r = '0.364). Subjects experienced a greater worsening in plasma ADMA levels while on PPI than on placebo, and this trend was more pronounced amongst those subjects with a history of vascular disease. However, these trends did not reach statistical significance, and PPI use was also not associated with an impairment in flow-mediated vasodilation during the course of this study. In conclusion, in this open-label, cross-over pilot study conducted among healthy subjects and coronary disease patients, PPI use did not significantly influence vascular endothelial function. Larger, long-term and blinded trials are needed to mechanistically explain the correlation between PPI use and adverse clinical outcomes, which has recently been reported in retrospective cohort studies.
AB - Proton pump inhibitors (PPIs) are commonly used drugs for the treatment of gastric reflux. Recent retrospective cohorts and large database studies have raised concern that the use of PPIs is associated with increased cardiovascular (CV) risk. However, there is no prospective clinical study evaluating whether the use of PPIs directly causes CV harm. We conducted a controlled, open-label, cross-over pilot study among 21 adults aged 18 and older who are healthy (n=11) or have established clinical cardiovascular disease (n=10). Study subjects were assigned to receive a PPI (Prevacid; 30 mg) or a placebo pill once daily for 4 weeks. After a 2-week washout period, participants were crossed over to receive the alternate treatment for the ensuing 4 weeks. Subjects underwent evaluation of vascular function (by the EndoPAT technique) and had plasma levels of asymmetric dimethylarginine (ADMA, an endogenous inhibitor of endothelial function previously implicated in PPI-mediated risk) measured prior to and after each treatment interval. We observed a marginal inverse correlation between the EndoPAT score and plasma levels of ADMA (r = '0.364). Subjects experienced a greater worsening in plasma ADMA levels while on PPI than on placebo, and this trend was more pronounced amongst those subjects with a history of vascular disease. However, these trends did not reach statistical significance, and PPI use was also not associated with an impairment in flow-mediated vasodilation during the course of this study. In conclusion, in this open-label, cross-over pilot study conducted among healthy subjects and coronary disease patients, PPI use did not significantly influence vascular endothelial function. Larger, long-term and blinded trials are needed to mechanistically explain the correlation between PPI use and adverse clinical outcomes, which has recently been reported in retrospective cohort studies.
KW - asymmetric dimethylarginine
KW - cardiovascular risk factors
KW - dimethylarginine dimethylaminohydrolase
KW - nitric oxide
KW - proton pump inhibitors
UR - http://www.scopus.com/inward/record.url?scp=84938766921&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84938766921&partnerID=8YFLogxK
U2 - 10.1177/1358863X14568444
DO - 10.1177/1358863X14568444
M3 - Article
C2 - 25835348
AN - SCOPUS:84938766921
SN - 1358-863X
VL - 20
SP - 309
EP - 316
JO - Vascular Medicine (United Kingdom)
JF - Vascular Medicine (United Kingdom)
IS - 4
ER -